Development of effective prevention and treatment strategies for atherosclerosis and osteoporosis present a major challenge to the biomedical research community in this country. Both are relatively silent disorders that frequently become manifest without warning in the form of acute myocardial infarction and fracture. Both are polygenic, age-dependent degenerative diseases. Both are common in the American population and their prevalence is increasing. Because they are common, both diseases are frequently observed in the same individual. Hence, it is imperative that treatment modalities for these diseases do not accelerate the course of the other disease. The general aim of this proposal is to determine whether the aminobisphosphonates, which are the most efficacious mode of increasing the bone mass and preventing fracture in patients with osteoporosis, will have any influence on the course of coronary artery plaque calcification. The Principal Investigator's hypothesis states that because 1] there are hydroxyapatite-resorbing cells in plaque just as there are in bone, 2] bisphosphonates inhibit the resorption process and 3] deposition of bisphosphonates occurs in calcified plaque just as it does in bone, these drugs will also inhibit plaque resorption resulting in a potentially dangerous increase in plaque mass. To examine this hypothesis, studies are proposed to examine the effects of alendronate, the only bisphosphonate currently approved for osteoporosis treatment and prevention, on arterial plaque calcification in vivo in two animal models of accelerated plaque calcification. In a second specific aim, the current 1-year analysis of coronary artery plaque calcification in patients before and after institution of alendronate therapy will be extended to a 3-year follow-up period. Stare-of-the-art technologies for imaging and reproducibly quantitating arterial hydroxyapatite content in both humans and animals will be employed. It is anticipated that these studies will 1] determine whether aminobisphosphonates like alendronate have any influence on the course of atherosclerotic plaque calcification, and 2] if so, set the stage for a more comprehensive analysis of the risk of plaque rupture and thrombosis in humans taking these drugs for the prevention and treatment of osteoporosis.